This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Understanding immune responses is critical tomaking progress in areas such as AIDS research. Results obtained during the past year have suggested the following: It was have found that YF-17D potently activates the innate immune system and dendritic cells by signaling through multiple TLRs, including TLR 2, 7/8 and 9, which are expressed on, and in, distinct DC subsets. (Human myeloid DCs express TLR 2 and 4, but do not express TLR 7 or 9. In contrast, plasmacytoid DCs express TLR 7 and 9, but do not express TLR 4). YF-17D does not however appear to signal through TLR 4 or TLR 3. This work was done using both human and murine dendritic cell subsets. Consistent with this, we found that YF-17D utilizes multiple TLR adaptor proteins (MyD88, TIRAP) in activating dendritic cells. Importantly, triggering TLR 7/8 and 9 is known to induce the anti-viral cytokine IFN-alpha;in contrast, triggering TLR 4 is known to induce abundant the Th1 inducing cytokine, IL-12p70, and emerging evidence is suggesting that triggering TLR 2 may induce Th2 cytokines. Consistent with this, YF-17D, which triggers multiple TLRs appeared to induce a broad spectrum of responses, including an IFN-alpha from PDCs, IL-12 from mDCs, IL-10, and a mixed Th1/Th2 profile. Injection of YF-17D into mice resulted in potent activation of multiple DC subsets, and up-regulation of costimulatory molecules. Regarding the quality of the adaptive immune response triggered by YF-17D, our strategy has been to perform some preliminary experiments in mice, using UF-17D, which expresses the class, I restricted OVA peptide SIINFEKL. Our data suggested that YF-OVA induces potent clonal expansion of OVA-specific CD8+ T cells, which secrete IL-2, IFN-gamma, IL-4, IL;-5 and IL-13 [unreadable]a mixed Th1/Th2 profile. This is consistent with the fact that YF-17D engages TLR 9, 7/8 (Th1 biasing), as well as TLR 2 (Th2 biasing).